Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) often begins with stimulant medications. The most widely prescribed are methylphenidate, amphetamines, and lisdexamfetamine. While all three work by enhancing dopamine and norepinephrine signaling in the brain, their mechanism of action, clinical efficacy, safety profile, and patient suitability differ in important ways. Recognizing these distinctions helps clinicians choose the right medication and tailor treatment to each patient’s unique needs.

1. Methylphenidate (MPH)

Mechanism of Action:

• Blocks the reuptake of dopamine and norepinephrine.

• Leads to increased concentration of these neurotransmitters in the synapse, improving attention and reducing hyperactivity.

Efficacy:

• Strong evidence base in children and adolescents.

• Slightly less robust effect sizes in adults compared to amphetamines.

Safety Profile:

• Common side effects: reduced appetite, insomnia, headache, mild increases in heart rate and blood pressure.

• Generally lower misuse potential than amphetamines.

Best Suited For:

• Children beginning stimulant therapy.

• Patients with comorbid anxiety (tends to exacerbate anxiety less than amphetamines).

• Situations where flexible dosing or shorter duration of action is needed.

2. Amphetamines (Mixed Amphetamine Salts)

Mechanism of Action:

• Not only block reuptake but also stimulate release of dopamine and norepinephrine from presynaptic neurons.

Efficacy:

• Often more potent than methylphenidate.

• Meta-analyses suggest higher response rates in adolescents and adults.

Safety Profile:

• Side effects: appetite suppression, insomnia, irritability, cardiovascular effects (BP/HR rise).

• Greater risk of misuse or diversion due to reinforcing properties.

Best Suited For:

• Adolescents and adults who do not respond well to methylphenidate.

• Patients requiring strong, sustained symptom control.

• Settings where misuse risk is carefully monitored.

3. Lisdexamfetamine (LDX)

Mechanism of Action:

• A prodrug of dextroamphetamine.

• Converted into its active form only after enzymatic processing in the blood, leading to a smooth onset and prolonged effect.

Efficacy:

• Comparable to or slightly superior to other stimulants, especially in adults.

• Provides consistent, all-day coverage.

Safety Profile:

• Lower abuse potential: inactive until metabolized, making it resistant to tampering.

• Side effects resemble those of amphetamines, but with less fluctuation due to its smoother release profile.

Best Suited For:

• Adolescents and adults needing once-daily, long-acting medication.

• Patients with concerns about misuse/diversion.

• Individuals who experienced “ups and downs” or mood crashes with other stimulants.

How to Choose Between Them?

• Children: Methylphenidate is usually first-line.

• Adolescents/Adults: Amphetamines or lisdexamfetamine may offer superior efficacy.

• Comorbid Anxiety: Methylphenidate tends to be tolerated better.

• Substance Misuse Concerns: Lisdexamfetamine is the safer option.

• Need for Flexible Dosing: Methylphenidate offers immediate and extended-release formulations.

Conclusion

Methylphenidate, amphetamines, and lisdexamfetamine are all highly effective in managing ADHD, but the right choice depends on patient age, comorbidities, lifestyle, and risk factors. Careful clinical evaluation, individualized dosing, and regular monitoring ensure both safety and effectiveness.

✦ About the Author
I’m Dr. Srinivas Rajkumar T, MD (AIIMS, New Delhi), Consultant Psychiatrist at Mind and Memory Clinic, Apollo Clinic, Velachery, Chennai (Opp. Phoenix Mall). My expertise spans ADHD, safe prescribing, and deprescribing strategies. I help patients and families navigate psychiatric treatments with clarity, safety, and confidence.

📍 Clinic Address: Apollo Clinic, 27/17 Velachery Road, Nagendra Nagar, Velachery, Chennai, Tamil Nadu – 600042
📞 Contact: +91 85951 55808